Statistical Analysis

We estimated that with a sample of 300 patients, the study would have 88% power to detect a 600-point difference between groups in the AUC of the patients' global assessment score and 88% power to detect a difference of 0.2 mg per deciliter (17.7 μmol per liter) in the change in the creatinine level between groups, on the basis of estimates of the variability in these outcome measures obtained from previous studies.18-20 With respect to the primary efficacy end point, we considered a 600-point difference to be a reasonable estimate of the minimum clinically important difference for this scale (see Section 3 in the Supplementary Appendix).

All analyses were performed according to the intention-to-treat principle. Owing to the use of two coprimary end points (an efficacy and a safety end point), the prespecified threshold for significance for each end point was a P value of less than 0.025. For secondary end points, a P value of less than 0.05 was considered to indicate statistical significance. The treatment groups defined by each treatment factor (mode and dose) were compared with the use of a linear model (for continuous end points), logistic regression (for binary end points), or a Cox model and Kaplan–Meier curves (for time-to-event end points). When differences between two groups that were defined by one of the treatment factors were assessed, the statistical model adjusted for the other factor. In the case of end points for which a relevant baseline value was measured (e.g., serum creatinine level), the analysis was also adjusted for the baseline value of that measure. A test for the presence of an interaction between the two treatment factors was also performed within the statistical framework appropriate for each end point.

RESULTS

Patient Population

A total of 308 patients were enrolled between March 2008 and November 2009 at 26 clinical sites in the United States and Canada (see Section 2 in the Supplementary Appendix). Baseline characteristics for each of the treatment groups are shown in Table 1 TABLE 1 Baseline Characteristics of the Study Participants, According to Treatment Group.. The mean age of the patients was 66 years; 27% were women, and 25% were black. The patient population had several high-risk features, including a history of hospitalization for heart failure within the previous 12 months (74% of the patients), moderate renal dysfunction (mean serum creatinine level, 1.5 mg per deciliter [132.6 μmol per liter]), and elevated natriuretic peptide levels (mean N-terminal pro-brain natriuretic peptide level, 7439 pg per milliliter). The mean ejection fraction was 35%, and 27% of patients had an ejection fraction of 50% or greater. The median time from presentation to randomization was 14.6 hours, and the median duration of study-drug administration was 65.3 hours.

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